Early stages of memory formation involve the activation of biochemical pathways that modulate neuronal communication. In particular, protein kinases play key roles in the synaptic changes that underlie forms of learning as diverse as short-term behavioral sensitization in invertebrates and long-lasting fear conditioning in mammals. As these roles become progressively clearer, it is becoming apparent that the contribution of different kinases is not fixed, but can vary as a result of prior experience and maturational stage. Modulation of transmission at the sensory neuron-motor neuron synapses of Aplysia contributes importantly to the changes induced by training in the defensive withdrawal reflex. Synaptic transmission is modulated by activity in the sensory neurons and by modulatory neurotransmitters. Synaptic facilitation, associated with behavioral sensitization, is caused by activation of protein kinases in the sensory neurons. At unstimulated synapses, facilitation is mediated primarily by protein kinase A (PKA), while facilitation that follows extensive stimulation is mediated mainly by protein kinase C (PKC). A similar change in the relative contributions of PKA and PKC to facilitation occurs as the animal matures. In addition, facilitation at synapses from mature animals varies with initial synaptic strength. The goals of this project are: 1) To define the physiological targets of the kinases contributing to plasticity: Which aspects of synaptic transmission are modulated by each kinase? 2) To characterize the change in the contributions of the kinases with stimulation: Are the kinases activated differently? Do their targets change? Does the sensitivity of the targets to the kinases change? 3) To determine whether there are synapse-specific differences in kinase involvement that resemble those between synapses of mature and immature animals: Does the variation in facilitation with synaptic strength result from differential contributions of the kinases or from a switch in their targets? Understanding the biological processes that underlie learning and memory would have implications for the treatment of disorders of memory, such as those that accompany Alzheimer's disease. Understanding how background factors such as prior experience and stage of maturation influence the formation of new memories could suggest how therapeutic strategies would need to be tailored to address the particular processes involved in memory formation in different behavioral and developmental states.